Succinic acid amide derivatives of nitro-substituted naphthalene ring, its preparation method and use
An alkyl and compound technology, applied in the preparation of carboxylic acid amides, carboxylic acid nitriles, and organic compounds, etc., can solve the problems of allopurinol liver and bone marrow toxicity, allergy, fulminant hepatitis, etc.
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Embodiment 1
[0029] .
[0030] A. Synthesis of Compound IV-1
[0031] 3.76g (20mmol) of compound II-1 and 2.64g (20mmol) of compound III were dissolved in 50mL of dry THF, stirred under cooling in an ice-water bath, and 4.13g (20mmol) of dicyclohexylcarbodiimide (DCC) and 4- Dimethylaminopyridine (DMAP) 0.61 g (5 mmol), then stirred at room temperature until the reaction was detected by TLC (within 12 h). The reaction mixture was poured into 300 mL of ice water, stirred, using 100 mL × 3 CH 2 Cl 2 Extract, combine the extract phases, successively wash with 100mL of 1% dilute hydrochloric acid and 100mL of 5% brine, and dry over anhydrous sodium sulfate. The desiccant was removed by suction filtration, the filtrate was evaporated to dryness on a rotary evaporator, and the obtained residue was purified by column chromatography to obtain compound IV-1, a white solid, ESI-MS, m / z=325 ([M+Na] + ).
[0032] B. Synthesis of Compound V-1
[0033] Compound IV-14.53g (15mmol) was dissolved i...
Embodiment 2-13
[0038] With reference to the operating steps of Example 1, the compounds listed in the following table were prepared:
[0039]
Embodiment 9
[0041] The compounds of the present invention and related compounds inhibit IC of URAT1 50 The values are determined in a similar manner as described in the literature (Example 12 in US2014 / 0005136). The results are listed below.
[0042] Construction of a cell line stably expressing the humanized URAT1 transporter: The humanized URAT1 gene (SLC22A112) was subcloned from the plasmid pCMV6-XL-5 (Origene) into the eukaryotic expression plasmid pCMV6 / neo (Origene). Gene sequencing confirmed that the humanized URAT1 was consistent with the information recorded in the gene bank (NM_144585.2). HEK293 human embryonic kidney cells (ATCC#CRL-1573) were cultured in EMEM tissue culture medium under 5% CO 2 and 95% air atmosphere. pCMV6 / Neo / URAT1 was transfected onto HEK293 cells using L2000 type transfection reagent (Invitrogene). After 24 hours, the transfected cells were divided into tissue culture dishes with a diameter of 10 cm, continued to grow for one day, and then the mediu...
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